The hospital dates from 1721, when it was founded by philanthropist Thomas Guy, who had made a fortune from the South Sea Bubble and as a publisher of unlicensed Bibles.[2] It was originally established as a hospital to treat "incurables" discharged from St Thomas' Hospital. Guy had been a Governor and benefactor of St Thomas' and his fellow Governors supported his intention by granting the south-side of St Thomas' Street for a peppercorn rent for 999 years.[2] Following his death in 1724, Thomas Guy was entombed at the hospital's chapel (also dating from the 18th century), in a tomb featuring a marble sculpture by John Bacon.[2]

The original buildings formed a courtyard facing St Thomas Street, comprising the hall on the east side and the Chapel, Matron's House and Surgeon's House on the west-side. A bequest of £180,000 by William Hunt in 1829, one of the largest charitable bequests in England in historic terms, allowed for a further hundred beds to be accommodated.[2] Hunt's name was given to the southern expansion of the hospital buildings which took place in 1850.[2] Two inner quadrangles were divided by a cloister which was later restyled and dedicated to the hospital's members who fell in the First World War. The east side comprised the care wards and the 'counting house' with the governors 'Burfoot Court Room'. The north-side quadrangle is dominated by a statue of Lord Nuffield (1877–1963) who was the chairman of governors for many years and also a major benefactor.[3]

Medical services at the Guy's site are now concentrated in the buildings to the east of Great Maze Pond: these buildings, which are connected, are known as Tower Wing, Bermondsey Wing, Southwark Wing and Borough Wing.[8] The Cancer Centre is in a separate building just to the south.[8] To the west of the Great Maze Pond is Guy's Campus which forms part of King's College London.[8]

At 148.65 metres (487.7 ft) high,[9] Guy's Tower (now called the Tower Wing) regained its tallest hospital building in the world status in 2014.[10] It has since been surpassed by the Outpatient Center at the Houston Methodist Hospital, in Houston, USA at 156.05 metres (512.0 ft).[11]